1. Field of the Invention
Applicant""s invention relates to medicaments and treatment procedures relating to fibrotic tissue maladies.
2. Background Information
A. Peyronie""s Disease
The initial focus of the present inventionxe2x80x94Peyronie""s diseasexe2x80x94has likely plagued men for time immemorial, but has been recognized as a distinct malady for no less than 400 years. Peyronie""s disease was first described in 1743 by a French surgeon, Francois de la Peyronie. The disease was written about as early as 1687 and was oftentimes associated with impotence.
Peyronie""s disease manifests itself in various manners, and to varying degrees of severity. The most common manifestation of Peyronie""s disease is in the form of a xe2x80x9clump,xe2x80x9d xe2x80x9cplaquexe2x80x9d or xe2x80x9chardxe2x80x9d area in the non-erect penis. With or without these palpable symptoms, painful erections and penile disfigurement are often associated with the malady.
The pain and disfigurement associated with Peyronie""s disease relate to the physical structure of the penis in which is found two erectile rods, called the corpora cavernosa, a conduit (the urethra) through which urine flows from the bladder, and the tunica which separates the cavernosa from the outer layers of skin of the penis. A person exhibiting Peyronie""s disease will have formation(s) of plaque or scar tissue between the tunica and these outer layers of the skin. The scarring or plaque accumulation of the tunica reduces its elasticity causes such that, in the affected area, it will not stretch to the same degree (if at all) as the surrounding, unaffected tissues. Thus, the erect penis bends in the direction of the scar or plaque accumulation, often with associated pain of some degree.
Peyronie""s disease often occurs in a mild form and heals spontaneously in 6 to 15 months. However, in severe cases, the hardened plaque substantially reduces penile flexibility and causes excruciating pain as the penis is forced into a highly arcuate or even serpentine configuration. A plaque on the top of the shaft (most common) causes the penis to bed upward; a plaque on the underside causes it to bend downward. In some cases, the plague develops on both top and bottom, leading to indentation and shortening of the penis.
In all but minor manifestations of Peyronie""s disease, the victim has some degree of sexual dysfunction. In more severe cases, sexual intercourse is either impossible, or is so painful as to be effectively prohibitive.
While plaque of Peyronie""s disease is itself benign, or noncancerous, this is of little solace to sufferers of the disease.
Reports indicate an incidence of Peyronie""s disease in no less than approximately one percent, to as high as three percent, of the male population. Although the disease occurs mostly in middle-aged men, younger and older men can acquire it. About 30 percent of men with Peyronie""s disease also develop fibrosis (hardened cells) in other elastic tissues of the body, such as on the hand or foot. A common example of such a condition is known as Dupuytren""s contracture of the hand.
Many researchers believe the plaque of Peyronie""s disease develops following trauma to the penis (hitting or bending) that causes localized bleeding inside the penis. If the penis is abnormally bumped or bent, an area where the septum attaches to the elastic fibers surrounding the corpora cavernosa may stretch beyond its normal limit, injuring the lining of the erectile chamber and, for example, rupturing small blood vessels. Also, as a result of aging, diminished elasticity near the point of attachment to the septum may tend to increase the chances of injury of this nature.
Such a damaged area may heal slowly or abnormally because of repeated trauma to the same area and/or because of the natural, minimal amount of blood-flow in the sheath-like fibers of the elastic structures of the penis. In cases of Peyronie""s disease which tend to heal within about a year, the plaque does not tend to advance beyond an initial inflammatory phase. In cases that persist for longer periods, the plaque typically undergoes fibrosis, or the formation of tough fibrous tissue, and even calcification, or the formation of calcium deposits.
While trauma might explain acute cases of Peyronie""s disease, it does not explain why most cases develop slowly and with no apparent traumatic event. It also does not explain why some cases disappear quickly, and why similar conditions, such as Dupuytren""s contracture, do not seem to result from severe trauma.
In some cases, men who are related by blood tend to develop Peyronie""s disease, which suggests a possible genetic predisposition to Peyronie""s disease.
B. Present Treatment
Until recently, the treatment of Peyronie""s disease was on a largely experimental basis. This was because the cause(s) and development of Peyronie""s disease were not well enough understood to provide effective relief and treatment.
Until recently, surgery was the only approach to treating Peyronie""s disease which appeared to have predictably repeatable efficacy. Surgery was, however, usually only indicated in long-term cases where the disease was stabilized and the deformity prevents intercourse and/or causes extreme pain. However, complications can and do often develop from surgery, including a permanent shortening of the penis.
Other approaches to treating Peyronie""s disease included simple plaque excision, described in the 19th century by MaClellan, Regnoli and Huitfield. By the early 20th century, however, most experts described this technique as disastrous. For this reason Young developed a procedure that simply xe2x80x9cfreedxe2x80x9d the plaque from the tunica albuginea in order to improve erectile dynamics. Lowsely and Boyce then re-explored the technique of simple plaque excision by adding the interposition of a xe2x80x98pat-padxe2x80x99 graft into the defect. Although many others continued to report success with this technique, it failed to gain general acceptance as the treatment of choice.
In 1995 Nesbit described the correction of congenital penile curvature with multiple elliptical excisions of the corporeal tunica. To this day, many surgeons prefer this technique for the correction of the Peyronie""s bend. However, the inevitable penile shortening led Devine and Horton (1974)to experiment with further grafting procedures. Having experimented with fascial, arterial and venous patches in dogs, they came to the conclusion that dermal grafts were the least likely to xe2x80x9ccontractxe2x80x9d and so reproduce the defect. To this day, many other grafting materials have been tried including autologous vein, temporoparietal fascia, tunica vaginalis, gortex and dacron.
The cost of the various surgical approaches to Peyronie""s disease (no less than around $6,500) is, alone, often a deterrent to many Peyronie""s disease sufferers in adopting this particular approach to treatment. While surgical intervention was, prior to the present invention, the most likely effective treatment in any given case of Peyronie""s disease, the condition does often reappear, even after surgery.
The other, recently advocated, non-surgical approaches to Peyronie""s disease treatment are many and varied, although they too were all largely ineffective. Attempts to dissolve the plaques by direct intra-lesional injections have been tried since the late 19th century. Walsham and Spencer injected both mercury and iodide and intra-lesional injections of fibrinolysins were used in the 1820""s. Teasley introduced the concept of intra-leasional steroid injections in 1954, although the pain caused by the high injection pressures led many surgeons to perform the procedure under general anesthetic. In 1959 Hinman developed a xe2x80x9chigh pressurexe2x80x9d screw-threaded injection device that was somewhat effective in certain cases, and could be used with no anaesthesia, but still lacked predictable efficacy. More recently, intra-lesional injections of agents such as Verapamil and clostridial collagenase have been tried, but with very limited success.
Of the injection methodologies, those involving clostridial collagenase appear to exhibit the most consistent efficacy, though still quite limited in effect and duration. Collagenase is likely effective through its ability to dissolve collagen, the major component of the plaque of Peyronie""s disease.
Both external beam radiation treatment and intra-lesional implantation of radium seeds have been tried since the turn of the 20th century. In 1921, Sonntag reviewed this practice and claimed that these treatments were actively detrimental. Despite this, radiation therapy had been used in many clinics over the years and some authorities still claim that success can be anticipated if a radiation regimen is initiated early in the course of the disease. Radiation treatment is also said to be particularly effective for treating patients whose predominant symptom is pain (as opposed to severe disfigurement).
As technologies have evolved, so have the associated energy sources which have been applied to treat Peyronie""s disease. Early in the 20th century, diathermy current was used to generate heat to treat the plaque and eventually low voltage electrical devices were developed and sold for use in the home. Perhaps the most imaginative variant was the technique known as histamine iontophoresis. This combined the use of electrodes with a xe2x80x9cplaque bustingxe2x80x9d solution that was supposedly absorbed into the penis when an electrical gradient was applied. In more recent times, both ultraviolet light and local ultrasound have surfaced and submerged in the treatment history.
Not surprisingly, the inevitable application of laser technology has recently emerged as a means of xe2x80x9cvaporizingxe2x80x9d the plaque. Again, the efficacy of this latest treatment is open to serious question.
The staggering array of treatment options for Peyronie""s disease (failed attempts, really), and the invested effort, cost and intellectual energy which they represent, are testament to the serious need that remains for an effective treatment for Peyronie""s disease, and one which patients can tolerate from cost, comfort and convenience perspectives.
All-in-all, until recently, there has simply been no truly effective treatment of Peyronie""s diseasexe2x80x94a disease which often produces such severe discomfort and distress that sufferers have been willing to endure such treatments as penile injections.
The recent change of fortunes for Peyronie""s disease sufferers came in the form of W. Jerry Easterling""s invention of a topical verapamil composition which, when applied topically to the penile shaft, proved remarkably effective in xe2x80x9cdissolvingxe2x80x9d Peyronie""s plaques. Since the introduction of Mr. Easterling""s topical verapamil compositions, the treatment for Peyronie""s disease has changed throughout the world. Known prescriptions for the composition have grown at approximately ten percent per month in the year prior to this application, with reported efficacy that eclipses any prior treatment, including even that involving the injecting of verapamil directly into Peyronie""s plaque (Levine). Notably, Levine himself has now prescribed Mr. Easterling""s composition for the treatment of Peyronie""s patients.
Mr. Easterling has also explored (with similar success) the use of topical calcium channel blocker compositions in the treatment of Dupuytren""s contracture of the hand and Ledderhose Fibrosis of the foot.
It is proposed that calcium channel blockers (including verapamil), when applied topically, migrate into the collagenous plaque of such fibrotic maladies as Peyronie""s disease, Dupuytren""s contracture of the hand and Ledderhose Fibrosis of the foot, and block the cellular entry of divalent calcium ions, thereby altering fibroblast metabolism which decreases the production of collagen. Simultaneously the production of collagenase is increased by the maturation of fibroblast collagenase. The collagenase causes degradation and remodeling of the fibrotic plaque. Due to the roles of divalent calcium and zinc in the production of collagenase, the collagenase is classified as a metaloprotease.
As the present inventor came to understand the apparent mechanism of action of calcium channel blockers in the treatment of fibrotic disease states, he postulated that other mechanisms which affect calcium utilization in the body might also be harnessed in the treatment of fibrotic disease states. Initial experimentation indicates that such is the case. Albeit with some side effects which, it is believed, can be alleviated to an acceptable degree with dosage modifications, the use of calmodulin blockers in treating Peyronie""s disease has proven efficacious.
It is an object of the present invention to provide a novel a medicament useful in the treatment of fibrotic tissue disorders, exemplified by Peyronie""s disease.
It is another object of the present invention to provide a novel and unobvious medicament useful in the treatment of fibrotic tissue disorders, exemplified by Peyronie""s disease, which medicament obviates the need for such dramatic treatments as intra-penile injections and surgery.
It is another object of the present invention to provide a novel and unobvious medicament useful in the treatment of fibrotic tissue disorders, exemplified by Peyronie""s disease, which medicament is more effective that existing means for treatment.
In satisfaction of these and related objectives, Applicant""s present invention provides a topical medicament and associated methodology for use thereof, through the use of which Peyronie""s disease may be effectively, cost effectively, and painlessly treated.